Identifying the driver miRNAs with somatic copy number alterations driving dysregulated ceRNA networks in cancers.

BACKGROUND: MicroRNAs (miRNAs) play critical roles in cancer initiation and progression, which were critical components to maintain the dynamic balance of competing endogenous RNA (ceRNA) networks. Somatic copy number alterations (SCNAs) in the cancer genome could disturb the transcriptome level of miRNA to deregulate this balance. However, the driving effects of SCNAs of miRNAs were insufficiently understood. METHODS: In this study, we proposed a method to dissect the functional roles of miRNAs under different copy number states and identify driver miRNAs by integrating miRNA SCNAs profile, miRNA-target relationships and expression profiles of miRNA, mRNA and lncRNA. RESULTS: Applying our method to 813 TCGA breast cancer (BRCA) samples, we identified 29 driver miRNAs whose SCNAs significantly and concordantly regulated their own expression levels and further inversely dysregulated expression levels of their targets or disturbed the miRNA-target networks they directly involved. Based on miRNA-target networks, we further constructed dynamic ceRNA networks driven by driver SCNAs of miRNAs and identified three different patterns of SCNA interference in the miRNA-mediated dynamic ceRNA networks. Survival analysis of driver miRNAs showed that high-level amplifications of four driver miRNAs (including has-miR-30d-3p, has-mir-30b-5p, has-miR-30d-5p and has-miR-151a-3p) in 8q24 characterized a new BRCA subtype with poor prognosis and contributed to the dysfunction of cancer-associated hallmarks in a complementary way. The SCNAs of driver miRNAs across different cancer types contributed to the cancer development by dysregulating different components of the same cancer hallmarks, suggesting the cancer specificity of driver miRNA. CONCLUSIONS: These results demonstrate the efficacy of our method in identifying driver miRNAs and elucidating their functional roles driven by endogenous SCNAs, which is useful for interpreting cancer genomes and pathogenic mechanisms.

Identifying the personalized driver gene sets maximally contributing to abnormality of transcriptome phenotype in glioblastoma multiforme individuals.

High heterogeneity in genome and phenotype of cancer populations made it difficult to apply population-based common driver genes to the diagnosis and treatment of cancer individuals. Characterizing and identifying the personalized driver mechanism for glioblastoma multiforme (GBM) individuals were pivotal for the realization of precision medicine. We proposed an integrative method to identify the personalized driver gene sets by integrating the profiles of gene expression and genetic alterations in cancer individuals. This method coupled genetic algorithm and random walk to identify the optimal gene sets that could explain abnormality of transcriptome phenotype to the maximum extent. The personalized driver gene sets were identified for 99 GBM individuals using our method. We found that genomic alterations in between one and seven driver genes could maximally and cumulatively explain the dysfunction of cancer hallmarks across GBM individuals. The driver gene sets were distinct even in GBM individuals with significantly similar transcriptomic phenotypes. Our method identified MCM4 with rare genetic alterations as previously unknown oncogenic genes, the high expression of which were significantly associated with poor GBM prognosis. The functional experiments confirmed that knockdown of MCM4 could significantly inhibit proliferation, invasion, migration, and clone formation of the GBM cell lines U251 and U118MG, and overexpression of MCM4 significantly promoted the proliferation, invasion, migration, and clone formation of the GBM cell line U87MG. Our method could dissect the personalized driver genetic alteration sets that are pivotal for developing targeted therapy strategies and precision medicine. Our method could be extended to identify key drivers from other levels and could be applied to more cancer types.

Applications of upconversion nanoparticles in cellular optogenetics.

Upconversion-mediated optogenetics is an emerging powerful technique to remotely control and manipulate the deep-tissue protein functions and signaling pathway activation. This technique uses lanthanide upconversion nanoparticles (UCNPs) as light transducers and through near-infrared light to indirectly activate the traditional optogenetic proteins. With the merits of high spatiotemporal resolution and minimal invasiveness, this technique enables cell-type specific manipulation of cellular activities in deep tissues as well as in living animals. In this review, we introduce the latest development of optogenetic modules and UCNPs, with emphasis on the integration of UCNPs with cellular optogenetics and their biomedical applications on the control of neural/brain activity, cancer therapy and cardiac optogenetics in vivo. Furthermore, we analyze the current developed strategies to optimize and advance the upconversion-mediated optogenetics and discuss the remaining challenges of its further applications in biomedical study and clinical translational research. STATEMENT OF SIGNIFICANCE: Optogenetics harnesses photoactivatable proteins to optically stimulate and control intracellular activities. UCNPs-mediated NIR-activatable optogenetics uses lanthanide upconversion nanoparticles (UCNPs) as light transducers and utilizes near-infrared (NIR) light to indirectly activate the traditional optogenetic proteins. The integration of UCNPs with cellular optogenetics has showed great promise in biomedical applications in regulating neural/brain activity, cancer therapy and cardiac optogenetics in vivo. The evolution and optimization of functional UCNPs and the discovery and engineering of novel optogenetic modules would both contribute to the advance of such unique hybrid technology, which may lead to discoveries in biomedical research and provide new treatments for human diseases.

Transcriptomic heterogeneity of driver gene mutations reveals novel mutual exclusivity and improves exploration of functional associations.

BACKGROUND: Lung adenocarcinoma (LUAD), as the most common subtype of lung cancer, is the leading cause of cancer deaths in the world. The accumulation of driver gene mutations enables cancer cells to gradually acquire growth advantage. Therefore, it is important to understand the functions and interactions of driver gene mutations in cancer progression. METHODS: We obtained gene mutation data and gene expression profile of 506 LUAD tumors from The Cancer Genome Atlas (TCGA). The subtypes of tumors with driver gene mutations were identified by consensus cluster analysis. RESULTS: We found 21 significantly mutually exclusive pairs consisting of 20 genes among 506 LUAD patients. Because of the increased transcriptomic heterogeneity of mutations, we identified subtypes among tumors with non-silent mutations in driver genes. There were 494 mutually exclusive pairs found among driver gene mutations within different subtypes. Furthermore, we identified functions of mutually exclusive pairs based on the hypothesis of functional redundancy of mutual exclusivity. These mutually exclusive pairs were significantly enriched in nuclear division and humoral immune response, which played crucial roles in cancer initiation and progression. We also found 79 mutually exclusive triples among subtypes of tumors with driver gene mutations, which were key roles in cell motility and cellular chemical homeostasis. In addition, two mutually exclusive triples and one mutually exclusive triple were associated with the overall survival and disease-specific survival of LUAD patients, respectively. CONCLUSIONS: We revealed novel mutual exclusivity and generated a comprehensive functional landscape of driver gene mutations, which could offer a new perspective to understand the mechanisms of cancer development and identify potential biomarkers for LUAD therapy.

Artificial Atomic Vacancies Tailor Near-Infrared II Excited Multiplexing Upconversion in Core-Shell Lanthanide Nanoparticles.

Epitaxial growth of an inert shell around the optical active lanthanide upconversion nanoparticles (UCNPs) is a general strategy to enhance their brightness. Yet, its potential as a tool in multiplexing emission tailoring has rarely been reported. Here, by developing the atomic vacancies into color selectivity actuators, we present an efficient strategy to achieve inert-shell-modulated multiplexing upconversion in 1540 nm activated UCNPs. Artificially generated fluoride atomic vacancies, owing to the decreased NaOH/NH4F dosage during shell growth, reduce the coordination number of Y-F and lattice densities in the inert shell, leading to the core-engineered shell nanoparticles with distinctive emission profiles. The multicolor tailoring is independent of shell thickness and can be readily applied to Lu3+/Gd3+-based shells. The upconversion emission can be exploited to visualize in security decoding and in vivo multiplexing bioimaging. This method of regulating atomic vacancies based on the inert-shell engineering opens new insights of upconversion modulation in core-shell lanthanide nanostructures.

Upconversion Nanoparticles-Based Multiplex Protein Activation to Neuron Ablation for Locomotion Regulation.

The optogenetic neuron ablation approach enables noninvasive remote decoding of specific neuron function within a complex living organism in high spatiotemporal resolution. However, it suffers from shallow tissue penetration of visible light with low ablation efficiency. This study reports a upconversion nanoparticle (UCNP)-based multiplex proteins activation tool to ablate deep-tissue neurons for locomotion modulation. By optimizing the dopant contents and nanoarchitecure, over 300-fold enhancement of blue (450-470 nm) and red (590-610 nm) emissions from UCNPs is achieved upon 808 nm irradiation. Such emissions simultaneously activate mini singlet oxygen generator and Chrimson, leading to boosted near infrared (NIR) light-induced neuronal ablation efficiency due to the synergism between singlet oxygen generation and intracellular Ca2+ elevation. The loss of neurons severely inhibits reverse locomotion, revealing the instructive role of neurons in controlling motor activity. The deep penetrance NIR light makes the current system feasible for in vivo deep-tissue neuron elimination. The results not only provide a rapidly adoptable platform to efficient photoablate single- and multiple-cells, but also define the neural circuits underlying behavior, with potential for development of remote therapy in diseases.

Lingual radicular rift valley in a mandibular right first premolar root: report of a rare case and review of the literature / Surco radicular lingual en la raíces del primer premolar mandibular derecho: reporte de un raro caso y revisión de la literatura

Irregular root configurations which often challenge the requirements of successful root canal treatments are always misleading doctors to incorrect clinical judgments and treatment planning. In this article we describe a rare case of CBCT C-shaped mandibular premolar with a huge area of invagination measuring 6 mm ´ 3 mm, which we termed a "radicular rift valley" from a 76-year-old man. Considering the complex process of differential diagnosis, the overall status of disease condition and the will of the patient we proposed five treatment plans and finally conservatively chose plan B composed of both RCT and periapical scaling. A related literature review is also added into this article to describe the whole situation of root invagination, to stress the importance of the vigilance of diagnosis and to provide reference views for future similar diseases.

Las configuraciones radiculares irregulares que a menudo desafían las exigencias de un tratamiento de canal radicular exitoso, son siempre engañosas llevando al especialista a juicios clínicos y planificación de tratamientos erróneos. En este artículo se describe, en un hombre de 76 años de edad, un raro caso de un premolar mandibular que mediante CBCT se observa la forma de C con un área enorme de invaginación midiendo 6 mm x 3 mm, lo que hemos denominado un "Rift valley radicular ". Teniendo en cuenta el complejo proceso de diagnóstico diferencial, el estado general de enfermedad y la voluntad del paciente, se propusieron cinco planes de tratamiento y, finalmente, se eligió el plan B conservador compuesto por el tratamiento del canal radicular y tratamiento periapical. Una revisión de la literatura relacionada se añade en este artículo para describir las situación de invaginación radicular, haciendo hincapié en la importancia del diagnóstico y para proporcionar referencias para enfermedades similares futuras.

Dextran glucosidase: a potential target of iminosugars in caries prevention.

It is well known that iminosugars are inhibitors of glycosyltransferases (GTFs) and glucosidases. Because of iminosugars' inhibitory effect on GTFs, scientists have made great effort to verify their roles in the prevention of caries. The inhibition of GTFs can reduce the synthesis of extracellular polysaccharides, especially the synthesis of water-insoluble α-1,3-linked glucan. Extracellular polysaccharides have a critical influence on the biofilm formation and virulence of the bacteria. However, another mechanism in which iminosugars can affect the biofilm is ignored. Extracellular polysaccharides are synthesized by bacteria via GTFs and modified by dextran glucosidase. Thus the authors propose that iminosugars be applied to caries prevention, which may involves in inhibiting the role of dextran glucosidase. The iminosugar can reduce glycosidases' hydrolysis of water-soluble α-1,6-linked glucan and raise the ration of α-1,6-linked glucan to α-1,3-linked glucan. As a result, it can change the components, structure and aqueous solubility of the biofilm extracellular polysaccharides, and finally reduce its cariogenicity. This will potentially decrease the incidence of dental caries, and improve the oral health.